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Cited by 180Genetic Associations and EpidemiologyGenetic and phenotypic traits in livestockGenetic Mapping and Diversity in Plants and Animals

Hidden heritability due to heterogeneity across seven populations

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Tropf, Felix C., Lee, S. Hong, Verweij, Renske M., Stulp, Gert, van der Most, Peter J., de Vlaming, Ronald, Bakshi, Andrew, Briley, Daniel A. +11 more·2017·Nature Human Behaviour
DOI 10.1038/s41562-017-0195-1PMC PMC5642946

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Abstract

Meta-analyses of genome-wide association studies (GWAS), which dominate genetic discovery are based on data from diverse historical time periods and populations. Genetic scores derived from GWAS explain only a fraction of the heritability estimates obtained from whole-genome studies on single populations, known as the 'hidden heritability' puzzle. Using seven sampling populations (N=35,062), we test whether hidden heritability is attributed to heterogeneity across sampling populations and time, showing that estimates are substantially smaller from across compared to within populations. We show that the hidden heritability varies substantially: from zero (height), to 20% for BMI, 37% for education, 40% for age at first birth and up to 75% for number of children. Simulations demonstrate that our results more likely reflect heterogeneity in phenotypic measurement or gene-environment interaction than genetic heterogeneity. These findings have substantial implications for genetic discovery, suggesting that large homogenous datasets are required for behavioural phenotypes and that gene-environment interaction may be a central challenge for genetic discovery.

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  • Imperfect genetic correlation across cohorts will be the norm for phenotypes that, like educational attainment, are environmentally contingent.

    “Our and others’ findings16,17 suggest that imperfect genetic correlation across cohorts will be the norm for phenotypes that, like EA, are environmentally contingent.”

    From Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals (2018) · cites this paper as [17]

    The Results (Best model by phenotype; page unavailable) find that birth cohort moderates genetic effects on educational attainment, supporting that example. But the same section finds no birth-cohort heterogeneity for the reproductive phenotypes, and the Discussion says genetic correlations across cohorts were not directly estimated. The paper therefore does not establish that imperfect correlations will be the norm for environmentally contingent phenotypes generally. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The finding of an imperfect genetic correlation replicates earlier results from smaller samples.

    “Our finding of an imperfect genetic correlation replicates earlier results from smaller samples16,17.”

    From Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals (2018) · cites this paper as [17]

    The Discussion reports limited evidence that genetic effects on reproductive behaviour in one country predict those in another, consistent with an imperfect cross-population genetic correlation. But it also says the study lacked the power to estimate genetic correlations directly; the correlations of 0.5–0.8 were used in simulations, not measured as a replicated finding. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Authors
Tropf, F. C., Lee, S. H., Verweij, R. M., Stulp, G., van der Most, P. J., de Vlaming, R., Bakshi, A., Briley, D. A., Rahal, C., Hellpap, R., Iliadou, A. N., Esko, T., Metspalu, A., Medland, S. E., Martin, N. G., Barban, N., Snieder, H., Robinson, M. R., & Mills, M. C.
Affiliations
  • University of Oxford (GB)
  • University of New England (AU)
  • University of Groningen (NL)
  • The University of Queensland (AU)
  • University of Illinois Urbana-Champaign (US)
  • Karolinska Institutet (SE)
  • University of Tartu (EE)
  • QIMR Berghofer Medical Research Institute (AU)
  • University Medical Center Groningen (NL)
Corresponding author
Tropf, Felix C.
ORCID
Venue
Nature Human Behaviour
Publisher
Springer Science and Business Media LLC
Published
2017-09-11
Volume
1
Issue
10
Pages
757-765
ISSN
2397-3374 (ISSN-L)
DOI
10.1038/s41562-017-0195-1
PMC
PMC5642946
OpenAlex
W2752326665
Cited by
180
References
10
Citations by year
2026: 7 · 2025: 11 · 2024: 12 · 2023: 17 · 2022: 24 · 2021: 14 · 2020: 55 · 2019: 9 · 2018: 22 · 2017: 5 · 2016: 4
FWCI
16.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Human Behaviour (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • IRIS (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • RUNE (Research UNE) (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • University of Washington
  • Johns Hopkins University (RC2 AG036495, RC4 AG039029)
  • Wellcome Trust (FP7/2007–2013, 01254)
  • QIMR Berghofer Medical Research Institute
  • International Seafood Sustainability Foundation
  • National Institute for Health and Care Research (FP7/2007–2013)
  • King's College London
  • European Commission (QLG2-CT-2002-01254, 2014‐2020, 2020 ‘, 654248, 2007–2013, FP7 2007-2013, HORIZON2020, 676550, 615603, FP7/2007, 01254, 692145)
  • Rijksuniversiteit Groningen
  • Stiftelsen för Strategisk Forskning
  • Eesti Teadusagentuur (IUT20-60, 2014-2020, FP7/2007-2013)
  • Nierstichting
  • Diabetes Fonds
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 480‐05‐003, 480- 05-003, FP7 2007-2013, 175.010.200, 175.010.2007.006)
  • Vetenskapsrådet (FP7/2007-2013, M-2005-1112)
  • Universitair Medisch Centrum Groningen
  • Tartu Ülikool
  • National Institutes of Health (HHSN268201100012C, FP7/2007-2013, HHSN268201100008C, HHSN268201100006C, 389875, DK U01-066134, HHSN26820- 1100005C, HHSN268201100007C, 2014-2020, HHSN268201100011C, EU/QLRT-2001-01254, HHSN268201100010C, HHSN268201100009C, QLG2-CT-2002-01254, AA10248, MH66206, AA13321, AA13320, DA12854, U01‐066134)
  • Medical Research Council (FP7/20072013)
  • Economic and Social Research Council (ES/N011856/1, 615603, FP7/2007-2013)
  • ESRC National Centre for Research Methods, University of Southampton (ES/N011856/1)
  • Australian Research Council (DP0343921)
  • National Health and Medical Research Council (A7960034, 496739, A79906588, 389927, 389891, 552485, DP0212016, 552498, 442981, 389938, 241944, 339462, 442915, 389875, A79801419, DP0770096, 389892)
  • European Regional Development Fund (2014-2020’, FP7/2007‐2013, 2007 – 2013)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA013321, R01AA013326, R01AA013320, R01AA014041, R01AA007535)
  • National Institute on Aging (RC2AG036495, AG036495, RC4AG039029, AG039029, U01AG009740)
  • National Heart, Lung, and Blood Institute (HHSN268201 100012C, HHSN268201100007I, HHSN268201100007C, HHSN2682 01100008C, HH-SN-268201100006C, HHSN268201100011C, HHSN2682011-00005I, HHSN2682011-­00009I, HHSN268201100005C, HHSN268201100005G, HHSN268201100010C, HHSN268201100011I, HHSN26820 1100009C, HHSN2682011-00008I)
  • National Institute of Mental Health (R01MH066206)
  • National Institute on Drug Abuse (R56DA012854, R01DA012854)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075787)
  • FP7 Ideas: European Research Council (615603)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
genetic heterogeneity, gene-environment interaction, population heterogeneity, genetic score, educational attainment, reproductive behavior, body mass index, height, age at first birth, number of children, complex traits, mega-analysis, behavioral phenotypes

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